KR100447033B1 - Novel 2-naphtamide derivatives and their use as therapeutic agents - Google Patents

Abstract

The present invention relates to 2-taphtamide derivatives in base or salt form corresponding to the general formula (I)

Wherein ZY represents an N—CH ₂ , C═CH or CH—CH ₂ group; R ¹ represents a hydrogen atom, a fluorine atom, a bromine atom or an iodine atom or a hydroxyl group, a methoxy group, a nitrile group or a nitro group; R ² represents a hydrogen atom or a bromine atom or a hydroxyl group, a methoxy group, a nitrile group or a nitro group; The R ₁ and R ₂ substituents are located together in the same ring of naphtamide units or each in one ring; R ³ and R ⁴ may be the same or different and each independently represent a hydrogen atom or a chlorine atom or a methoxy group or a methyl group or an electron withdrawing group.

The present invention also relates to a therapeutic use of the dopamine D ₃ receptor as a local agonist. The present invention applies to the treatment of neuropsychiatric diseases involving dopamine D ₃ receptors, in particular psychosis and depression, the treatment of drug dependence or the treatment of sexual disorders.

Description

Novel 2-naphtamide derivatives and their use as therapeutics

The present invention relates to novel compounds derived from 2-naphtamide and to their use as therapeutics, in particular as selective dopamine.

Many phenylpiperazine derivatives are known and are used because of their activity on the central nervous system, in particular their neurosuppressive properties.

Phenylpiperazine is essentially known as serotonergic factor.

As for the dopamine receptor, some of the arylpiperazine derivatives have been shown to exhibit a high affinity for the dopamine D ₃ receptor compared to other dopamine receptors (see Murray PJ et al., Bioorganic & Medicinal Chemistry Letters, vol. 5). , No. 3, pp 219-222 (1995).

According to this reference, these compounds, which show some selectivity for the dopamine D ₃ receptor relative to other receptors, may provide an effective anti-psychotic agent in which the selective antagonist of the dopamine D ₃ receptor has no extracorporeal side effects. Can be used to confirm the hypothesis that it can.

Moreover, some naphtamide derivatives act as pure antagonists of the D ₃ receptor and thus can be used in the preparation of a medicament that is an antagonist of dopamine by blocking the D ₃ receptor (French patent application 91 13103).

Recently, naphtamide derivatives of arylpiperazine have been disclosed in US Pat. No. 5, 395,835 as selective antagonists of the D ₃ receptor. These compounds are useful as antipsychotics and for the treatment of diseases associated with dopaminergic blockade.

The inventors have shown that 2-naphtamide derivatives of the general formula (I) have a strong affinity for dopaminergic receptors, especially the D3 receptor, and selectively act as strong local agonists of dopamine at these D ₃ receptors. Has been exemplified in surprising and unexpected ways.

Accordingly, the present invention relates to 2-naphtamide derivatives, in base or salt form, corresponding to the general formula (I):

Wherein ZY represents an N—CH ₂ C═CH or CH—CH ₂ group; R ¹ represents a hydrogen atom, a fluorine atom, a bromine atom or an iodine atom or a hydroxyl group, a methoxy group, a nitrile group or a nitro group; R ² represents a hydrogen atom or a bromine atom or represents a hydroxyl group, a methoxy group, a nitrile group or a nitro group; The R ₁ and R ₂ substituents are located together in the same ring of naphtamide units or each in one ring; R ³ and R ⁴ may be the same or different and each independently represent a hydrogen atom or a chlorine atom or a methoxy group or a methyl group or an electron-withdrawing group.

The present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a pharmaceutically acceptable excipient and at least one derivative of formula (I) in the form of a base or in the form of a pharmaceutically acceptable salt.

The present invention also relates to a medicament acting as a local agonist of the dopamine D ₃ receptor containing at least one derivative of the general formula (I) as an active element, It is about a use.

Derivatives according to the invention are represented by general formula (I). These compounds are novel.

Naphtamide derivatives of arylpiperazine are disclosed in U. S. Patent No. 5,395, 835 described above, while among these compounds, the piperazine unit is separated from the naphtamide unit by a chain comprising two carbon atoms, The chain according to the invention represents four carbon atoms.

The derivatives according to the invention can be provided in the form of a free base or in the form of salts, in particular in the form of addition salts with physiologically acceptable acids, and the invention also applies various forms thereof.

According to the invention, derivatives in which ZY represents an N-CH ₂ group are preferred.

As specific preferred derivatives according to the invention, the following compounds may be mentioned.

N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-4-nitro-2-naphtamide; N- [4- (4-phenyl-1,2,3,6-tetrahydropyridinyl) butyl] -2-naphtamide; N- [4- (4-phenylpiperidinyl) butyl] -2-naphtamide; N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-4-cyano-2-naphtamide; N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -2-naphtamide; N- [4- (4- (2-chlorophenyl) piperazinyl) butyl] -3-methoxy-2-naphtamide; N- [4- (4- (2-chlorophenyl) piperazinyl) butyl] -2-naphtamide; N- [4- (4- (3-chlorophenyl) piperazinyl) butyl] -2-naphtamide; N- [4- (4-phenylpiperazinyl) butyl] -2-naphtamide; N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-2-naphtamide oxalate.

Derivatives of formula (I) according to the invention can be prepared according to known methods (W. Adcock et al., Aust. J. Chem., 1965, 18, 1351).

Suitably substituted acid sites (2-naphthoic acid) are converted to mixed anhydrides by isobutylchloroformate in acetone or other solvents in the basic medium and reacted with the desired amines as shown in the following scheme. do :

Other methods for activating carboxyl functional groups can also be used; In fact, any process for preparing amides, including the use of corresponding acid chlorides, is suitable.

A type B aminopiperazine is obtained by a conventional method in which an alkylation reaction with chlorobutyronitrile in a basic medium is carried out in an alcoholic solvent using a compatible phenylpiperazine as a starting material. The nitrile functional group is then reduced to the primary amine by catalytic hydrogenation in the presence of LiAlH ₄ or Pd / charcoal.

Aminobutylphenyltetrahydropyridine of type C or aminobutylphenylpiperidine of type D is a commercially available product or N-Boc-4-piperidone (where Boc means tert-butoxycarbonyl) ) Is reacted with a phenylmagnesium derivative and then dehydrated to obtain a conventional method for obtaining the corresponding tetrahydropyridine. The corresponding piperidine is obtained by catalytic hydrogenation of the latter compound. t-butoxycarbonyl (Boc) protection is hydrolyzed in acidic medium and nitrogen is alkylated to bromobutyronitrile in basic medium according to the method described above. The process for preparing Compound C and Compound D is as follows:

The present invention is explained in more detail through the following examples, which are intended to illustrate but not limit the invention.

Example

Example 1 Preparation of N- [4- (4- (2-methoxyphenyl) -piperazinyl) butyl] -1-methoxy-4-nitro-2-naphtamide (Do 885)

120 mg of 1-methoxy-4-nitronaphthalene-2-carboxylic acid A (prepared according to a) below) is dissolved in 15 ml of anhydrous acetone in a 25 ml two-necked flask. 2.5 equivalents of triethylamine are added and the mixture is cooled to -15 [deg.] C. using a dry ice / acetone vessel. Then 1.05 equiv of isobutylchloroformate is added to the mixture and reacted at -15 占 폚 for 1 hour. Then 1.05 equiv of N- (4-aminobutyl) -N '-(2-methoxyphenyl) piperazine B (prepared according to b) below) is added and reacted for 2 hours at room temperature under an inert atmosphere. Triethylamine hydrochloride is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in a small amount of ethyl acetate, and naphtamide is purified by chromatography on a silica column (eluent: ethyl acetate / methyl alcohol 90/10). Naphtamide is crystallized from diethyl ether and 85 mg of yellow crystals. Is obtained.

Analysis result C ₂₇ H ₃₂ N ₄ O ₅

Theoretic% C 65.84,% H 6.55,% N 11.37

Found% C 66.25,% H 6.43,% N 11.12

a) Preparation of 1-methoxy-4-nitro-2-naphthoic acid (A)

Methyl Ester of -1-methoxy-2-naphthoic Acid

1.88 g (10 mmol) of 1-hydroxy-2-naphthoic acid are suspended in 50 ml of methyl ethyl ketone. 2.76 g (2 equivalents) of anhydrous potassium carbonate was added, and then 2.51 g (2 equivalents) of dimethyl sulfate was added dropwise. The mixture was heated to reflux with stirring overnight, then cooled, excess potassium carbonate was filtered off and the filtrate was concentrated. The evaporated residue is dissolved in water and extracted several times with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated. Purification is carried out by chromatography on a silica column (eluent: hexane / ethyl acetate 90/10). Golden oil is obtained. Y = 82%

Methyl Ester of -1-methoxy-4-nitro-2-naphthoic acid

2 g of methyl ester of 1-methoxy-2-naphthoic acid are dissolved in 15 ml of glacial acetic acid. 1.2 equivalents of concentrated nitric acid are added dropwise into the solution in glacial acetic acid and reacted with stirring well for 4 hours at room temperature. The reaction mixture is slowly hydrolyzed in ice. Methyl ester of 1-methoxy-4-nitro-2-naphthoic acid precipitates. The precipitate is filtered off, washed several times with ice-cold water, dissolved again with ethyl acetate, washed with water and washed with saturated potassium carbonate solution (Note 1) to remove residual acetic acid and finally Wash with water. The mixture is dried over sodium sulfate and aggregated. Purification is carried out by chromatography on silica columns (eluent: hexane / CH ₂ Cl ₂ , 60/40).

Yellow crystal: Y = 89%, Melting point: 110 ℃,

Note 1: Sodium hydroxide is undesirable to use because it produces highly colored complexes that are difficult to remove. Since the neutralization of acetic acid against K ₂ CO ₃ generates carbon dioxide, it is important to thoroughly wash the precipitate beforehand to remove as much acid as possible.

-1-methoxy-4-nitro-2-naphthoic acid (A)

750 mg of methyl ester of 1-methoxy-4-nitro-2-naphthoic acid is dissolved in 20 ml of methine.

1.5 equivalents of sodium hydrogen carbonate are added and the mixture is heated to reflux for 10 hours. The mixture is concentrated and the residue is dissolved in water. Extract with ether to remove organic impurities and acidify with 5N hydrochloric acid solution to pH = 2. An yellowish white precipitate is obtained. Extract with ethyl acetate, wash three times with water, dry over sodium sulfate, and aggregate the mixture. Acid is crystallized from pentane. Purification is carried out by recrystallization with hot water, and activated carbon is added to remove impurities. Yellowish white crystals. Y = 94%.

b) Preparation of N- (4-aminobutyl) -N '-(2-methoxyphenyl) piperazine (B)

-N- (2-methoxyphenyl) -N '-(3-cyanopropyl) piperazine

8 g of N- (2-methoxyphenyl) piperazine is suspended in 150 ml of acetonitrile. After adding 2.5 equivalents of anhydrous potassium carbonate, 1.05 equivalents of 4-bromobutyronitrile are added dropwise as a solution in acetonitrile. The mixture is heated to reflux for 10 hours, then filtered and the filtrate is concentrated. The residue is dissolved in ethyl acetate and washed three times with water. The organic phase is extracted with 1M hydrochloric acid solution and the acid phase is washed with ethyl acetate. The acidic phase is neutralized with 28% aqueous ammonia to a pH> 11. Extract with ethyl acetate, wash the organic phase with water, dry over anhydrous sodium sulfate and aggregate the mixture. Nitrile is crystallized from hexane and recrystallized from the same solvent in the hot state. 6.8 g of nitrile are obtained. Y = 75%.

-N- (4-aminobutyl) -N '-(2-methoxyphenyl) piperazine (B)

1.2 g of lithium aluminum hydride is divided into small portions (exothermic dissolution) and suspended in 50 ml of anhydrous diethyl ether (freshly distilled through sodium). 5 g of N- (2-methoxyphenyl) -N '-(3-cyanopropyl) piperazine was added dropwise as a solution in anhydrous tetrahydrofuran (THF) and heated to reflux for 2 hours. The mixture is hydrolyzed with a mixture of 5 ml of water in 25 ml of THF and left overnight to allow aggregation to precipitate. The precipitate is filtered over celite, the filtrate is dried over anhydrous sodium sulfate and the filtrate is aggregated. Y = 81%.

Example 2 Preparation of N- [4- (4-phenyl-1,2,3,6-tetrahydro pyridinyl) butyl] -2-naphtamide (Do 911)

250 mg of naphthalene-2-carboxylic acid A (2-naphthoic acid) are suspended in 20 ml of anhydrous dichloromethane (freshly distilled through CaH ₂ ). Add 1.2 equivalents of oxaryl chloride at 0 ° C., then add 2 drops of anhydrous dimethyl formamide (to catalyze the chlorination reaction) and then proceed with vigorous stirring for 1 hour at room temperature under an inert atmosphere (argon). . The mixture is concentrated to remove solvent and excess oxaryl chloride, and the resulting acid chloride is redissolved in 20 ml of dichloromethane. N- (4-aminobutyl) -4-phenyl-1,2,3,6-tetrahydropyridine C 1.05 equiv. (Prepared according to C below) is added and 2 at room temperature under inert atmosphere (argon) The reaction proceeds for a time. The mixture is concentrated and the residue is dissolved in 3M hydrochloric acid solution. The acidic phase is washed with ethyl acetate and the aqueous phase is neutralized with 32% aqueous ammonia to pH> 11. Extract with ethyl acetate, wash the organic phase several times with water, dry over sodium sulfate and aggregate the mixture. The residue is crystallized from 50/50 ether / hexane mixtures. 280 mg of white crystals are obtained. Y = 50%.

c) preparation of N- (4-aminobutyl) -4-phenyl-1,2,3,6-tetrahydropyridine (c)

-4- (4-phenyl-1,2,3,6-tetrahydropyridinyl) -butyronitrile

5 g of 4-phenyl-1,2,3,6-tetrahydropyridinehydrochloride (a very toxic compound; J. med., 1983. 309, 310; Science, 1983, 219, 979; Psychiatry Res. 1979, 1, 249) and 100 ml of acetonitrile are placed in a 250 ml round bottom flask. After adding 2.5 equivalents of anhydrous potassium carbonate, 1.05 equivalents of 4-bromobutyronitrile are added dropwise into a solution in acetonitrile. The mixture is heated to reflux for 16 hours, filtered, the paste is washed with acetone and the filtrate is condensed. The residue is dissolved in ethyl acetate and washed three times with water. The organic phase is extracted with 3M hydrochloric acid solution and the acidic phase is washed with ethyl acetate. The acidic phase is neutralized with 28% aqueous ammonia to a pH> 11. Extract with ethyl acetate, wash the organic phase with water, dry over anhydrous sodium sulfate and condense the mixture. Nitrile is purified by chromatography on a silica column (eluent: ethyl acetate / hexane 80/20). Obtain white crystals. Melting point = 57-59 ° C. Y = 79%.

-N- (4-aminobutyl) -4-phenyl-1,2,3,6-tetrahydropyridine (C)

1.8 g of lithium aluminum hydride is divided in small portions (pyrolysis) and suspended in 50 ml of dry THP (freshly distilled through sodium). 4.5 g of 4- (4-phenyl-1,2,3,6-tetrahydropyridinyl) butyronitrile was added dropwise at 0 ° C. with a solution in THF, followed by stirring at 0 ° C. for 3 hours. . The mixture is hydrolyzed into a mixture of 5 ml of water in THE 50 ml and the mixture is left overnight to agglomerate the precipitate. The precipitate is filtered over celite and the filtrate is dried over anhydrous sodium sulfate and condensed. The residue is vacuum distilled with a vacuum pump. Colorless oil is obtained. Y = 86%.

Example 3: Preparation of N- (4- (4-phenylpiperidinyl) -butyl) -2-naphtide (Do 912)

120 mg of N- [4- (4-phenyl-1,2,3,6-tetrahydropyridinyl) butyl] -2-naphtamide obtained according to Example 2 was added to 20 ml of methanol in a 100 ml Parr bottle. Dissolve.

Add one tablespoon of Pd / C (Palladicum-on-Charcoal) to the end of the spatula and proceed with the hydrogenation reaction as a Parr apparatus for six hours under pressure of 60 psi.

The catalyst is filtered off, rinsed with methanol and the filtrate is condensed. Purification is carried out by chromatography on a silica column (eluent: ethyl acetate / methanol 9/10). Crystallization is carried out with hexane to give 110 mg of white crystals.

Y = 91%. Melting point = 143-144 ° C.

Analysis: C ₂₆ H _3O N ₂ O

Theoretic:% C 80.79,% H 7.82,% N 7.25

Experimental Value:% C 80.66,% H 7.89,% N 7.22

Example 4: Preparation of N- [4- (4- (2-methoxyphenyl) -piperazinyl) butyl] -1-methoxy-4-cyano-2-naphtide (883)

120 mg of 1-methoxy-4-cyanonaphthalene-2-carboxylic acid (prepared according to Example 1a) is dissolved in 20 ml of anhydrous acetone. 2.5 equivalents of triethylamine are added and the mixture is cooled to -15 ° C using a dry ice / acetone bath. 1.05 equiv of isobutyl chloroformate is added and the reaction proceeds at -15 [deg.] C. for 1 hour. 1.05 equivalents of N- (4-aminobutyl) -N '-(2-methoxyphenyl) piperazine (prepared according to Example Ib) is added and the reaction is allowed to proceed for 2 hours at room temperature under an inert atmosphere. Triethylamine hydrochloride is filtered off and the filtrate is evaporated to dryness. The evaporated residue is dissolved in a small amount of ethyl acetate, and naphtamide is purified by chromatography on silica column (eluent: ethyl acetate / methanol 90/10). Naphtamide is crystallized from diethyl ether. 76 mg of white crystals are obtained. Y = 23%. Melting point = 128 ° C.

Example 5

N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -2-naphtamide

Melting Point = 121 ° C., C ₂₆ H ₃₁ N ₃ O ₂ (DO 897)

Example 6

N- [4- (4- (2-chlorophenyl) piperazinyl) butyl] -3-methoxy-2-naphtamide

Melting Point = 86 ° C., C ₂₆ H ₃₀ N ₃ O ₂ Cl (DO 917)

Example 7

N- [4- (4- (2-chlorophenyl) piperazinyl) butyl] -2-naphtamide

Melting Point = 107-109 ° C, C25H28CIN3O (DO 910)

Example 8

N- [4- (4- (3-chlorophenyl) piperazinyl) butyl] -2-naphtamide

Melting Point = 150-152 ° C., C ₂₅ H ₂₈ CIN ₃ O (DO 908)

Example 9

N- [4- (4- (phenylpiperazinyl) butyl] -2-naphtamide

Melting Point = 164 ° C., C ₂₅ H ₂₅ N ₃ O (DO 905)

Example 10

N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-2-naphtamide oxalate Melting point = 164 ° C., C ₂₇ H ₃₄ N ₃ O ₃ C ₂ H ₂ O ₄ (897a)

Biological activity

The activity of the derivatives of general formula (I) according to the present invention can be expressed in cells expressing human recombinant dopaminergic receptors; The degree of stimulation that can be determined by measuring the incorporation of [3H] -thymidine; CHO cells expressing the D _2s receptor and NG 108-15 cells expressing the D ₃ receptor were evaluated (see Eur. J. Pharmacol. Mol. Phannacol. Sect., 1994, 268: 129 by Philon et al.). -139 (Sutel et al., Neuroreport, 1995, 6: 329-332).

Among these derivatives, some exhibit greater affinity for the D ₃ receptor compared to the D ₂ receptor.

Nahwa dot fluoride (nafadotride) Type (Note: the above-mentioned French patent application No. 91 13 103 Ho) compounds of are contrary to the behavior as a pure antagonist of the D ₃ receptor, the present inventors have found that, unexpectedly in that D ₃ receptors, the compounds of the invention It was found that they act as potent local agonists of dopamine and their intrinsic activity varies between 50% and 80% (dopamine = 100%). Thus, the compound of Example 5 has an endogenous activity of 60% and an effective concentration of 50% thereof is 3 nM. This same compound exhibits a pronounced affinity for the D ₂ receptor 25 times smaller than that for the D ₃ receptor; As a result it consists of the latter highly selective (local) agonists.

In addition, the inventors have also found that minimal structural differences among the compounds described herein can result in significant changes in the selectivity and intrinsic activity of the molecule. For example, when R ₃ and R ₄ each represent a methoxy group, this distribution leads to selectivity of the D ₃ receptor / D ₂ receptor that will be lost when compared to monosubstitution. Moreover, the presence of chlorine substituents (R ₃ or R ₄ ) will significantly reduce the affinity of derivative (I) for the D ₃ receptor.

These properties lead to therapeutic use that is not yet encountered with existing dopaminergic agents.

Indeed, the high selectivity of the molecules is extravertebral, selective of dopaminergic delivery of the marginal region involved in emotional and cognitive processes, without interfering on the dopaminergic transmssions of the pituitary or lobe postrema system Enable activation (expressed as the D ₃ receptor).

Therefore, they must prevent extraneous, side effects of existing compounds related to the latter effects on the anterior pit and trophic domains. In addition, the nature of the local D ₃ agonist (partial agonist D ₃₎ is to be normalized to dopaminergic transmission without the risk of excessive activation.

Thus, the derivatives of the present invention can be used for the manufacture of medicaments and drugs for the treatment of neuropsychiatric diseases comprising the D ₃ receptor, such as psychosis or depression.

Furthermore, to explain the role of the D ₃ receptor in drug-dependent conditions, drugs and drugs based on these derivatives enhance the withdrawal-related conditions and / or detoxification in patients dependent on cocaine, heroin, alcohol, nicotine, etc. It can be usefully administered when it can be done.

The derivatives according to the invention are also effective in penile erection and can also be used in the manufacture of medicaments and drugs for the treatment of sexual disorders, in particular for the treatment of impotence. Like the agonists of the D ₃ receptor, the derivatives according to the invention can also be used for the complementary treatment of Parkinson's disease by L-DOPA.

Thus, the present invention relates to such complementary medicines, as well as the use of agonists of the D ₃ receptor comprising the novel product of the invention, for the manufacture of a medicine for the complementary treatment of Parkinson's disease.

This activity is related to the discovery related to an animal model of Parkinson's disease in which treatment with L-DOPA induces expression in cells of the striatum of the D ₃ receptor, which predicts sensitization to the motor action of L-DOPA. It can be explained by.

The derivatives of general formula (I) according to the invention can be administered orally, in particular in the form of pharmaceutical compositions.

The therapeutically effective dosage may vary for various derivatives, but for the compound of Example 5, the dosage is 0.05-5 mg / kg for oral use.

Claims (7)

2-naphtamide derivatives in base or salt form corresponding to the general formula (I) Wherein ZY represents an N—CH ₂ , C═CH or CH—CH ₂ group; R ¹ represents a hydrogen atom, a fluorine atom, a bromine atom or an iodine atom or a hydroxyl group, a methoxy group, a nitrile group or a nitro group; R ² represents a hydrogen atom or a bromine atom or a hydroxyl group, a methoxy group, a nitrile group or a nitro group; The R ₁ and R ₂ substituents are located together in the same ring of naphtamide units or each in one ring; R ³ and R ⁴ may be the same or different and each independently represent a hydrogen atom or a chlorine atom or a methoxy group or a methyl group or an electron withdrawing group. The derivative of claim 1, wherein ZY is an N-CH ₂ group. The compound according to claim 1, further comprising: N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-4-nitro-2-naphtamide; N- [4- (4-phenyl-1,2,3,6-tetrahydropyridinyl) butyl] -2-naphtamide; N- [4- (4-phenylpiperidinyl) butyl] -2-naphtamide; N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-4-cyano-2-naphtamide; N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -2-naphtamide; N- [4- (4- (2-chlorophenyl) piperazinyl) butyl] -3-methoxy-2-naphtamide; N- [4- (4- (2-chlorophenyl) piperazinyl) butyl] -2-naphtamide; N- [4- (4- (3-chlorophenyl) perferazinyl) butyl] -2-naphtamide; N- [4- (4-phenylpiperazinyl) butyl] -2-naphtamide; N- [4- (4- (2-methoxyphenyl) piperazinyl) butyl] -1-methoxy-2-naphtamide oxalate. A derivative characterized in that the compound is selected from the group consisting of. Dopamine, characterized in that it contains a pharmaceutically acceptable excipient and a therapeutically effective amount of at least one derivative in the form of a base according to any one of claims 1 to 3 or in the form of a pharmaceutically acceptable salt. Pharmaceutical compositions for the treatment of neuropsychiatric diseases, drug dependence, or sexual disorders involving the D3 receptor. A medicament for complementary treatment of Parkinson's disease, comprising as an active ingredient the derivative of any one of claims 1 to 3, which acts as an agonist of the dopamine D ₃ receptor. The method according to claim 4, for the treatment of psychosis and depression as a neuropsychiatric disorder, withdrawal, detoxification, or withdrawal and detoxification in patients with cocaine, heroin, alcohol, or nicotine dependence as drug dependence, or sexual dysfunction as a sexual disorder. Pharmaceutical composition characterized by. The pharmaceutical composition according to claim 4, which is for complementary treatment of Parkinson's disease.